Do We Need a New Hypothesis for KATP Closure in β-Cells? Distinguishing the Baby From the Bathwater

Abstract

Let us first start where we all agree: KATP channels are the main conductance of the resting pancreatic b-cell, and their closure by changes in the ATP-to-ADP ratio is the triggering mechanism used by glucose to increase Ca21 flux into the b-cell (1–3). When Cook and Hales (4) and Ashcroft et al. (5) discovered the KATP channel and showed it was closed by glucose metabolism, the source of the ATP that closed the channel was not stipulated. In fact, we struggled to find the first references to the term consensus model or canonical model in the literature. This is not mere semantics, as it seems most parsimonious to us that both glycolytic and mitochondrially derived ATP should be capable of closing the channel. As Merrins and Kibbey (6) argue in their Counterpoint article in this issue of Diabetes, it is difficult to separate glycolysis from oxidative phosphorylation (OXPHOS) because they are tightly linked: inhibiting glycolysis will also affect mitochondria by depriving them of pyruvate